Cerebrovascular reactivity MRI as a biomarker for cerebral small vessel disease-related cognitive decline: Multi-site validation in the MarkVCID Consortium.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

BACKGROUND: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease. OBJECTIVE: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. METHODS: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. RESULTS: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. CONCLUSIONS: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Cross-Vendor Test-Retest Validation of Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS) for Evaluating Glymphatic System Function.

The diffusion tensor image analysis along the perivascular space (DTI-ALPS) method was proposed to evaluate glymphatic system (GS) function. However, few studies have validated its reliability and reproducibility. Fifty participants' DTI data from the MarkVCID consortium were included in this study. Two pipelines by using DSI studio and FSL software were developed for data processing and ALPS index calculation. The ALPS index was obtained by the average of bilateral ALPS index and was used for testing the cross-vendor, inter-rater and test-retest reliability by using R studio software. The ALPS index demonstrated favorable inter-scanner reproducibility (ICC=0.77 to 0.95, P < 0.001), inter-rater reliability (ICC=0.96 to 1, P< 0.001) and test-retest repeatability (ICC=0.89 to 0.95, P< 0.001), offering a potential biomarker for in vivo evaluation of GS function.

Peak width of skeletonized mean diffusivity and cognitive performance in cerebral amyloid angiopathy.

Background: Cerebral Amyloid Angiopathy (CAA) is a cerebral small vessel disease that can lead to microstructural disruption of white matter (WM), which can be measured by the Peak Width of Skeletonized Mean Diffusivity (PSMD). We hypothesized that PSMD measures would be increased in patients with CAA compared to healthy controls (HC), and increased PSMD is associated with lower cognitive scores in patients with CAA. Methods: Eighty-one probable CAA patients without cognitive impairment who were diagnosed with Boston criteria and 23 HCs were included. All subjects underwent an advanced brain MRI with high-resolution diffusion-weighted imaging (DWI). PSMD scores were quantified from a probabilistic skeleton of the WM tracts in the mean diffusivity (MD) image using a combination of fractional anisotropy (FA) and the FSL Tract-Based Spatial Statistics (TBSS) algorithm (www.psmd-marker.com). Within CAA cohort, standardized z-scores of processing speed, executive functioning and memory were obtained. Results: The mean of age and sex were similar between CAA patients (69.6 ± 7.3, 59.3% male) and HCs (70.6 ± 8.5, 56.5% male) (p = 0.581 and p = 0.814). PSMD was higher in the CAA group [(4.13 ± 0.94) × 10-4 mm2/s] compared to HCs [(3.28 ± 0.51) × 10-4 mm2/s] (p < 0.001). In a linear regression model corrected for relevant variables, diagnosis of CAA was independently associated with increased PSMD compared to HCs (ß = 0.45, 95% CI 0.13-0.76, p = 0.006). Within CAA cohort, higher PSMD was associated with lower scores in processing speed (p < 0.001), executive functioning (p = 0.004), and memory (0.047). Finally, PSMD outperformed all other MRI markers of CAA by explaining most of the variance in models predicting lower scores in each cognitive domain. Discussion: Peak Width of Skeletonized Mean Diffusivity is increased in CAA, and it is associated with worse cognitive scores supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA. As a robust marker, PSMD can be used in clinical trials or practice.

Placental growth factor as a sensitive biomarker for vascular cognitive impairment.

INTRODUCTION: High-performing biomarkers measuring the vascular contributions to cognitive impairment and dementia are lacking. METHODS: Using a multi-site observational cohort study design, we examined the diagnostic accuracy of plasma placental growth factor (PlGF) within the MarkVCID Consortium (n = 335; CDR 0-1). Subjects underwent clinical evaluation, cognitive testing, MRI, and blood sampling as defined by Consortium protocols. RESULTS: In the prospective population of 335 subjects (72.2 ± 7.8 years of age, 49.3% female), plasma PlGF (pg/mL) shows an ordinal odds ratio (OR) of 1.16 (1.07-1.25; P = .0003) for increasing Fazekas score and ordinal OR of 1.22 (1.14-1.32; P < .0001) for functional cognitive impairment measured by the Clinical Dementia Rating scale. We achieved the primary study outcome of a site-independent association of plasma PlGF (pg/mL) with white matter injury and cognitive impairment in two of three study cohorts. Secondary outcomes using the full MarkVCID cohort demonstrated that plasma PlGF can significantly discriminate individuals with Fazekas ≥ 2 and CDR = 0.5 (area under the curve [AUC] = 0.74) and CDR = 1 (AUC = 0.89) from individuals with CDR = 0. DISCUSSION: Plasma PlGF measured by standardized immunoassay functions as a stable, reliable, diagnostic biomarker for cognitive impairment associated with substantial white matter burden.

Improving detection of cerebral small vessel disease aetiology in patients with isolated lobar intracerebral haemorrhage.

BACKGROUND AND PURPOSE: We evaluate whether non-haemorrhagic imaging markers (NHIM) (white matter hyperintensity patterns, lacunes and enlarged perivascular spaces (EPVS)) can discriminate cerebral amyloid angiopathy (CAA) from hypertensive cerebral small vessel disease (HTN-cSVD) among patients with isolated lobar intracerebral haemorrhage (isolated-LICH). METHODS: In patients with isolated-LICH, four cSVD aetiologic groups were created by incorporating the presence/distribution of NHIM: HTN-cSVD pattern, CAA pattern, mixed NHIM and no NHIM. CAA pattern consisted of patients with any combination of severe centrum semiovale EPVS, lobar lacunes or multiple subcortical spots pattern. HTN-cSVD pattern consisted of any HTN-cSVD markers: severe basal ganglia PVS, deep lacunes or peribasal ganglia white matter hyperintensity pattern. Mixed NHIM consisted of at least one imaging marker from either pattern. Our hypothesis was that patients with HTN-cSVD pattern/mixed NHIM would have a higher frequency of left ventricular hypertrophy (LVH), which is associated with HTN-cSVD. RESULTS: In 261 patients with isolated-LICH, CAA pattern was diagnosed in 93 patients, HTN-cSVD pattern in 53 patients, mixed NHIM in 19 patients and no NHIM in 96 patients. The frequency of LVH was similar among those with HTN-cSVD pattern and mixed NHIM (50% vs 39%, p=0.418) but was more frequent in HTN-cSVD pattern compared with CAA pattern (50% vs 20%, p<0.001). In a regression model, HTN-cSVD pattern (OR: 7.38; 95% CI 2.84 to 19.20) and mixed NHIM (OR: 4.45; 95% CI 1.25 to 15.90) were found to be independently associated with LVH. CONCLUSION: Among patients with isolated-LICH, NHIM may help differentiate HTN-cSVD from CAA, using LVH as a marker for HTN-cSVD.

MRI free water as a biomarker for cognitive performance: Validation in the MarkVCID consortium.

Introduction: To evaluate the clinical validity of free water (FW), a diffusion tensor imaging-based biomarker kit proposed by the MarkVCID consortium, by investigating the association between mean FW (mFW) and executive function. Methods: Baseline mFW was related to a baseline composite measure of executive function (EFC), adjusting for relevant covariates, in three MarkVCID sub-cohorts, and replicated in five, large, independent legacy cohorts. In addition, we tested whether baseline mFW predicted accelerated EFC score decline (mean follow-up time: 1.29 years). Results: Higher mFW was found to be associated with lower EFC scores in MarkVCID legacy and sub-cohorts (p-values < 0.05). In addition, higher baseline mFW was associated significantly with accelerated decline in EFC scores (p = 0.0026). Discussion: mFW is a sensitive biomarker of cognitive decline, providing a strong clinical rational for its use as a marker of white matter (WM) injury in multi-site observational studies and clinical trials of vascular cognitive impairment and dementia (VCID).

External ventricular drain placement is associated with lower mortality after intracerebral hemorrhage with intraventricular hemorrhage.

BACKGROUND AND AIMS: Many patients with intracerebral hemorrhage (ICH) develop intraventricular hemorrhage (IVH), which is associated with higher mortality and worse clinical outcome. External ventricular drains (EVDs) are often placed, but there is little data on how much patients benefit from this intervention. We explored the use, timing, and location of EVD in ICH patients and any association with clinical outcome. RESULTS: During the study period, 2870 patients presented with primary ICH, and 2486 were included in analyses. Overall, patients were 73 (± 13) years old; 54% were male, and 46% had associated IVH. An EVD was placed in 29% of patients with IVH and 4% of those without. IVH patients with EVD were younger (67 ± 13 vs 74 ± 13, p < 0.001), had larger IVH volumes (17 mL vs 8 mL, p < 0.001), and lower GCS scores (7 vs 10, p < 0.001), compared to those without EVD. Ninety-day mortality was available in 2486 (100%) patients, while 90-day mRS was available in 1673 (67.3%). In univariate analysis, EVD placement was associated with lower likelihood of 90-day mortality (53% vs 59%, p = 0.048) but higher likelihood of poor outcome (88% vs 85%, p < 0.001) in those for whom this was available. Those with poor outcomes underwent faster EVD placement (0.46 days vs. 0.96 days, p = 0.01). In multivariate analysis, EVD placement was associated with lower 90-day mortality (OR 0.19, 95% CI 0.053-0.657, p = 0.009), but not with lower odds of poor outcome (OR 1.64, 95% CI 0.508-5.309, p = 0.4). In multivariate analysis, days to EVD placement was associated with lower 90-day mortality (OR 0.69, 95% CI 0.49-0.96, p = 0.027). CONCLUSION: IVH is relatively common after ICH. After controlling for potential confounds, EVD placement is associated with lower mortality, but not clearly with better neurologic outcome. In addition, more rapid EVD placement is associated with higher mortality, potentially reflecting early development of herniation or obstructive hydrocephalus.

Postacute Sequelae of COVID-19 Critical Illness.

With an ever-increasing number of COVID-19 survivors, providers are tasked with addressing the longer lasting symptoms of COVID-19, or postacute sequelae of SARS-CoV-2 infection (PASC). For critically ill patients, existing knowledge about postintensive care syndrome (PICS) represents a useful structure for understanding PASC. Post-ICU clinics leverage a multidisciplinary team to evaluate and treat the physical, cognitive, and psychological sequelae central to both PICS and PASC in critically ill patients. While management through both pharmacologic and nonpharmacologic modalities can be used, further research into both the optimal treatment and prevention of PASC represents a key public health imperative.

Cerebellar atrophy and its implications on gait in cerebral amyloid angiopathy.

OBJECTIVE: Recent data suggest that cerebral amyloid angiopathy (CAA) causes haemorrhagic lesions in cerebellar cortex as well as subcortical cerebral atrophy. However, the potential effect of CAA on cerebellar tissue loss and its clinical implications have not been investigated. METHODS: Our study included 70 non-demented patients with probable CAA, 70 age-matched healthy controls (HCs) and 70 age-matched patients with Alzheimer's disease (AD). The cerebellum was segmented into percent of cerebellar subcortical volume (pCbll-ScV) and percent of cerebellar cortical volume (pCbll-CV) represented as percent (p) of estimated total intracranial volume. We compared pCbll-ScV and pCbll-CV between patients with CAA, HCs and those with AD. Gait velocity (metres/second) was used to investigate gait function in patients with CAA. RESULTS: Patients with CAA had significantly lower pCbll-ScV compared with both HC (1.49±0.1 vs 1.73±0.2, p<0.001) and AD (1.49±0.1 vs 1.66±0.24, p<0.001) and lower pCbll-CV compared with HCs (6.03±0.5 vs 6.23±0.6, p=0.028). Diagnosis of CAA was independently associated with lower pCbll-ScV compared with HCs (p<0.001) and patients with AD (p<0.001) in separate linear regression models adjusted for age, sex and presence of hypertension. Lower pCbll-ScV was independently associated with worse gait velocity (ß=0.736, 95% CI 0.28 to 1.19, p=0.002) in a stepwise linear regression analysis including pCbll-CV along with other relevant variables. INTERPRETATION: Patients with CAA show more subcortical cerebellar atrophy than HC or patients with AD and more cortical cerebellar atrophy than HCs. Reduced pCbll-ScV correlated with lower gait velocity in regression models including other relevant variables. Overall, this study suggests that CAA causes cerebellar injury, which might contribute to gait disturbance.

Instrumental validation of free water, peak-width of skeletonized mean diffusivity, and white matter hyperintensities: MarkVCID neuroimaging kits.

Introduction: To describe the protocol and findings of the instrumental validation of three imaging-based biomarker kits selected by the MarkVCID consortium: free water (FW) and peak width of skeletonized mean diffusivity (PSMD), both derived from diffusion tensor imaging (DTI), and white matter hyperintensity (WMH) volume derived from fluid attenuation inversion recovery and T1-weighted imaging. Methods: The instrumental validation of imaging-based biomarker kits included inter-rater reliability among participating sites, test-retest repeatability, and inter-scanner reproducibility across three types of magnetic resonance imaging (MRI) scanners using intra-class correlation coefficients (ICC). Results: The three biomarkers demonstrated excellent inter-rater reliability (ICC >0.94, P-values < .001), very high agreement between test and retest sessions (ICC >0.98, P-values < .001), and were extremely consistent across the three scanners (ICC >0.98, P-values < .001). Discussion: The three biomarker kits demonstrated very high inter-rater reliability, test-retest repeatability, and inter-scanner reproducibility, offering robust biomarkers suitable for future multi-site observational studies and clinical trials in the context of vascular cognitive impairment and dementia (VCID).

Survival After Severe COVID-19: Long-Term Outcomes of Patients Admitted to an Intensive Care Unit.

BACKGROUND: Understanding the long-term sequelae of severe COVID-19 remains limited, particularly in the United States. OBJECTIVE: To examine long-term outcomes of patients who required intensive care unit (ICU) admission for severe COVID-19. DESIGN, PATIENTS, AND MAIN MEASURES: This is a prospective cohort study of patients who had severe COVID-19 requiring an ICU admission in a two-hospital academic health system in Southern California. Patients discharged alive between 3/21/2020 and 12/31/2020 were surveyed approximately 6 months after discharge to assess health-related quality of life using Patient-Reported Outcomes Measurement Information System (PROMIS®)-29 v2.1, post-traumatic stress disorder (PTSD) and loneliness scales. A preference-based health utility score (PROPr) was estimated using 7 PROMIS domain scores. Patients were also asked their attitude about receiving aggressive ICU care. KEY RESULTS: Of 275 patients admitted to the ICU for severe COVID-19, 205 (74.5%) were discharged alive and 132 (64%, median age 59, 46% female) completed surveys a median of 182 days post-discharge. Anxiety, depression, fatigue, sleep disturbance, ability to participate in social activities, pain interference, and cognitive function were not significantly different from the U.S. general population, but physical function (44.2, SD 11.0) was worse. PROPr mean score of 0.46 (SD 0.30, range -0.02 to 0.96 [<0 is worse than dead and 1 represents perfect health]) was slightly lower than the U.S. general population, with an even distribution across the continuum. Poor PROPr was associated with chronic medical conditions and receipt of life-sustaining treatments, but not demographics or social vulnerability. PTSD was suspected in 20% and loneliness in 29% of patients. Ninety-eight percent of patients were glad they received life-saving treatment. CONCLUSION: Most patients who survive severe COVID-19 achieve positive outcomes, with health scores similar to the general population at 6 months post-discharge. However, there is marked heterogeneity in outcomes with a substantial minority reporting severely compromised health.

Characteristics of Post-ICU and Post-COVID Recovery Clinics in 29 U.S. Health Systems.

The multifaceted long-term impairments resulting from critical illness and COVID-19 require interdisciplinary management approaches in the recovery phase of illness. Operational insights into the structure and process of recovery clinics (RCs) from heterogeneous health systems are needed. This study describes the structure and process characteristics of existing and newly implemented ICU-RCs and COVID-RCs in a subset of large health systems in the United States. DESIGN: Cross-sectional survey. SETTING: Thirty-nine RCs, representing a combined 156 hospitals within 29 health systems participated. PATIENTS: None. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: RC demographics, referral criteria, and operating characteristics were collected, including measures used to assess physical, psychologic, and cognitive recoveries. Thirty-nine RC surveys were completed (94% response rate). ICU-RC teams included physicians, pharmacists, social workers, physical therapists, and advanced practice providers. Funding sources for ICU-RCs included clinical billing (n = 20, 77%), volunteer staff support (n = 15, 58%), institutional staff/space support (n = 13, 46%), and grant or foundation funding (n = 3, 12%). Forty-six percent of RCs report patient visit durations of 1 hour or longer. ICU-RC teams reported use of validated scales to assess psychologic recovery (93%), physical recovery (89%), and cognitive recovery (86%) more often in standard visits compared with COVID-RC teams (psychologic, 54%; physical, 69%; and cognitive, 46%). CONCLUSIONS: Operating structures of RCs vary, though almost all describe modest capacity and reliance on volunteerism and discretionary institutional support. ICU- and COVID-RCs in the United States employ varied funding sources and endorse different assessment measures during visits to guide care coordination. Common features include integration of ICU clinicians, interdisciplinary approach, and focus on severe critical illness. The heterogeneity in RC structures and processes contributes to future research on the optimal structure and process to achieve the best postintensive care syndrome and postacute sequelae of COVID outcomes.

Effect of vascular amyloid on white matter disease is mediated by vascular dysfunction in cerebral amyloid angiopathy.

We postulated that vascular dysfunction mediates the relationship between amyloid load and white matter hyperintensities (WMH) in cerebral amyloid angiopathy (CAA). Thirty-eight cognitively healthy patients with CAA (mean age 70 ± 7.1) were evaluated. WMH was quantified and expressed as percent of total intracranial volume (pWMH) using structural MRI. Mean global cortical Distribution Volume Ratio representing Pittsburgh Compound B (PiB) uptake (PiB-DVR) was calculated from PET scans. Time-to-peak [TTP] of blood oxygen level-dependent response to visual stimulation was used as an fMRI measure of vascular dysfunction. Higher PiB-DVR correlated with prolonged TTP (r = 0.373, p = 0.021) and higher pWMH (r = 0.337, p = 0.039). Prolonged TTP also correlated with higher pWMH (r = 0.485, p = 0.002). In a multivariate linear regression model, TTP remained independently associated with pWMH (p = 0.006) while PiB-DVR did not (p = 0.225). In a bootstrapping model, TTP had a significant indirect effect (ab = 0.97, 95% CI: 0.137-2.461), supporting that the association between PiB-DVR and pWMH is mediated by TTP response. There was no longer a direct effect independent of the hypothesized pathway. Our study suggests that the effect of vascular amyloid load on white matter disease is mediated by vascular dysfunction in CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.

Cerebral Small Vessel Disease and Depression Among Intracerebral Hemorrhage Survivors.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is an acute manifestation of cerebral small vessel disease (CSVD), usually cerebral amyloid angiopathy or hypertensive arteriopathy. CSVD-related imaging findings are associated with increased depression incidence in the general population. Neuroimaging may, therefore, provide insight on depression risk among ICH survivors. We sought to determine whether CSVD CT and magnetic resonance imaging markers are associated with depression risk (before and after ICH), depression remission, and effectiveness of antidepressant treatment. METHODS: We analyzed data from the single-center longitudinal ICH study conducted at Massachusetts General Hospital. Participants underwent CT and magnetic resonance imaging imaging and were followed longitudinally. We extracted information for neuroimaging markers of CSVD subtype and severity. Outcomes of interest included pre-ICH depression, new-onset depression after ICH, resolution of depressive symptoms, and response to antidepressant treatment. RESULTS: We followed 612 ICH survivors for a median of 47.2 months. Multiple CSVD-related markers were associated with depression risk. Survivors of cerebral amyloid angiopathy-related lobar ICH were more likely to be diagnosed with depression before ICH (odds ratio, 1.68 [95% CI, 1.14-2.48]) and after ICH (sub-hazard ratio, 1.52 [95% CI, 1.12-2.07]), less likely to achieve remission of depressive symptoms (sub-hazard ratio, 0.69 [95% CI, 0.51-0.94]), and to benefit from antidepressant therapy (P=0.041). Cerebral amyloid angiopathy disease burden on magnetic resonance imaging was associated with depression incidence and treatment resistance (interaction P=0.037), whereas hypertensive arteriopathy disease burden was only associated with depression incidence after ICH. CONCLUSIONS: CSVD severity is associated with depression diagnosis, both before and after ICH. Cerebral amyloid angiopathy-related ICH survivors are more likely to experience depression (both before and after ICH) than patients diagnosed with hypertensive arteriopathy-related ICH, and more likely to report persistent depressive symptoms and display resistance to antidepressant treatment.

Trends in Endotracheal Intubation During In-Hospital Cardiac Arrests: 2001-2018.

OBJECTIVES: Airway management during in-hospital cardiac arrest represents a fundamental component of resuscitative efforts, yet little is known about temporal trends in intubation during in-hospital cardiac arrest. Our objective was to investigate changes in in-hospital cardiac arrest airway management over time and in response to national guideline updates. DESIGN: Observational cohort study of a prospectively collected database. SETTING: Multicenter study of hospitals participating in the "Get With The Guidelines-Resuscitation" registry from January 1, 2001, to December 31, 2018. SUBJECTS: Adult patients who experienced an in-hospital cardiac arrest and did not have an invasive airway in place prior to the arrest. INTERVENTIONS: The primary outcome was the rate of intra-arrest intubation from 2001 to 2018. We constructed multivariable regression models with generalized estimating equations to determine the annual adjusted odds of intubation. We also assessed the timing of intubation relative to the onset of pulselessness and other arrest measures. We used an interrupted time-series analysis to assess the association between the 2010 Advanced Cardiac Life Support guideline update and intubation rates. MEASUREMENTS AND MAIN RESULTS: One thousand sixty-six eight hundred patients from 797 hospitals were included. From 2001 to 2018, the percentage of patients intubated during an arrest decreased from 69% to 55% for all rhythms, 73% to 60% for nonshockable rhythms, and 58% to 36% for shockable rhythms (p < 0.001 for trend for all 3 groups). The median time from onset of pulselessness to intubation increased from 5 minutes in 2001 (interquartile range, 2-8 min) to 6 minutes in 2018 (interquartile range, 4-10 min) (p < 0.001 for trend). Following the 2010 guideline update, there was a downward step change and a steeper decrease over time in the rate of intubation as compared to the preintervention period (p < 0.001). CONCLUSIONS: Endotracheal intubation rates during in-hospital cardiac arrest have decreased significantly over time, with a more substantial decline following the updated 2010 guideline that prioritized chest compressions over airway management.

Idiopathic primary intraventricular hemorrhage and cerebral small vessel disease.

BACKGROUND: Although primary intraventricular hemorrhage is frequently due to trauma or vascular lesions, the etiology of idiopathic primary intraventricular hemorrhage (IP-IVH) is not defined. AIMS: Herein, we test the hypothesis that cerebral small vessel diseases (cSVD) including hypertensive cSVD (HTN-cSVD) and cerebral amyloid angiopathy are associated with IP-IVH. METHODS: Brain magnetic resonance imaging from consecutive patients (January 2011 to September 2019) with non-traumatic intracerebral hemorrhage from a single referral center were reviewed for the presence of HTN-cSVD (defined by strictly deep or mixed-location intracerebral hemorrhage/cerebral microbleeds) and cerebral amyloid angiopathy (applying modified Boston criteria). RESULTS: Forty-six (4%) out of 1276 patients were identified as having IP-IVH. Among these, the mean age was 74.4 ± 12.2 years and 18 (39%) were females. Forty (87%) had hypertension, and the mean initial blood pressure was 169.2 ± 40.4/88.8 ± 22.2 mmHg. Of the 35 (76%) patients who received a brain magnetic resonance imaging, two (6%) fulfilled the modified Boston criteria for possible cerebral amyloid angiopathy and 10 (29%) for probable cerebral amyloid angiopathy. Probable cerebral amyloid angiopathy was found at a similar frequency when comparing IP-IVH patients to the remaining patients with primary intraparenchymal hemorrhage (P-IPH) (27%, p = 0.85). Furthermore, imaging evidence for HTN-cSVD was found in 8 (24%) patients with IP-IVH compared to 209 (28%, p = 0.52) patients with P-IPH. CONCLUSIONS: Among IP-IVH patients, cerebral amyloid angiopathy was found in approximately one-third of patients, whereas HTN-cSVD was detected in 23%-both similar rates to P-IPH patients. Our results suggest that both cSVD subtypes may be associated with IP-IVH.

Intensive Blood Pressure Lowering and DWI Lesions in Intracerebral Hemorrhage: Exploratory Analysis of the ATACH-2 Randomized Trial.

BACKGROUND: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. METHODS: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139 mm Hg versus 140-179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. RESULTS: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00-5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71-1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. CONCLUSIONS: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

Latent profile analysis of cognitive decline and depressive symptoms after intracerebral hemorrhage.

BACKGROUND: Cognitive impairment and depressive symptoms are highly prevalent after Intracerebral Hemorrhage (ICH). We leveraged Latent Profile Analysis (LPA) to identify profiles for cognitive decline and depression onset after ICH. We also investigated differences in clinical, genetic and neuroimaging characteristics across patients' profiles. METHODS: We analyzed data from the ICH study conducted at Massachusetts General Hospital between January 1998 and December 2019. We collected information from electronical health records, follow-up interviews, CT and MRI imaging, and APOE genotype. We conducted LPA and multinomial logistic regression analyses to: 1) identify distinct profiles for cognitive decline and depression onset after ICH; 2) identify clinical, neuroimaging and genetic factors predicting individuals' likelihood to express a specific profile. RESULTS: We followed 784 ICH survivors for a median of 45.8 months. We identified four distinct profiles in cognitive and depressive symptoms after ICH: low depression and dementia risk, early-onset depression and dementia, late-onset depression and dementia, high depression with low dementia risk. Cerebral small vessel disease severity and APOE genotype were specifically associated with the late-onset profile (both p < 0.05). Acute hematoma characteristics (size, intraventricular extension) and functional disability were specifically associated with the early-onset profile (all p < 0.05). CONCLUSION: We identified four distinct profiles for cognitive and depressive symptoms after ICH, each displaying specific associations with individual patients' clinical, genetic and neuroimaging data. These associations reflect separate biological mechanisms influencing dementia and depression risk after ICH. Our findings support employing LPA in future ICH studies, and is likely applicable to stroke survivors at large.

Computed Tomography Angiography Spot Sign, Hematoma Expansion, and Functional Outcome in Spontaneous Cerebellar Intracerebral Hemorrhage.

Background and Purpose: The computed tomography angiography spot sign is associated with hematoma expansion, case fatality, and poor functional outcome in spontaneous supratentorial intracerebral hemorrhage (ICH). However, no data are available on the spot sign in spontaneous cerebellar ICH. Methods: We investigated consecutive patients with spontaneous cerebellar ICH at 3 academic hospitals between 2002 and 2017. We determined patient characteristics, hematoma expansion (>33% or 6 mL), rate of expansion, discharge and 90-day case fatality, and functional outcome. Poor functional outcome was defined as a modified Rankin Scale score of 4 to 6. Associations were tested using univariable and multivariable logistic regression. Results: Three hundred fifty-eight patients presented with cerebellar ICH, of whom 181 (51%) underwent a computed tomography angiography. Of these 181 patients, 121 (67%) were treated conservatively of which 15 (12%) had a spot sign. Patients with a spot sign treated conservatively presented with larger hematoma volumes (median [interquartile range]: 26 [7­41] versus 6 [2­13], P=0.001) and higher speed of expansion (median [interquartile range]: 15 [24­3] mL/h versus 1 [5­0] mL/h, P=0.034). In multivariable analysis, presence of the spot sign was independently associated with death at 90 days (odds ratio, 7.6 [95% CI, 1.6­88], P=0.037). With respect to surgically treated patients (n=60, [33%]), 14 (23%) patients who underwent hematoma evacuation had a spot sign. In these 60 patients, patients with a spot sign were older (73.5 [9.2] versus 66.6 [15.4], P=0.047) and more likely to be female (71% versus 37%, P=0.033). In a multivariable analysis, the spot sign was independently associated with death at 90 days (odds ratio, 2.1 [95% CI, 1.1­4.3], P=0.033). Conclusions: In patients with spontaneous cerebellar ICH treated conservatively, the spot sign is associated with speed of hematoma expansion, case fatality, and poor functional outcome. In surgically treated patients, the spot sign is associated with 90-day case fatality.